Metabolic dysfunction-associated steatotic liver disease (MASLD), one of the most prevalent chronic diseases worldwide [1], is characterized by excessive fat build-up in the liver, with or without inflammation and fibrosis. Although its progression to cirrhosis or hepatocellular carcinoma significantly contributes to mortality, only one drug has been approved [2], highlighting the urgent need for identifying additional therapeutic targets. Recently, with the shift in nomenclature from non-alcoholic fatty liver disease [3], metabolic dysfunction has garnered attention as a key factor in MASLD pathology [4]. Obviously, alterations of lipid metabolism are clearly linked to the initial course of the disease, namely steatosis. For instance, genetic predisposition and comorbidities disrupting normal lipid metabolism are known as major risk factors [5,6]. In addition, losing weight is known to be of benefit at every stage of MASLD, not only reducing lipid accumulation but also alleviating inflammation and fibrosis [7].

Given that 75% of excess hepatic triacylglyceride derives from extrahepatic milieu, with a relatively smaller contribution (25%) of de novo lipogenesis [8], enhancing lipid catabolism may represent an appealing therapeutic strategy. Validity of this approach is further supported by the successful clinical trial of resmetirom, a thyroid hormone receptor β agonist, which promotes fatty acid oxidation [2]. As a key enzyme initiating fatty acid oxidation, acyl-CoA synthetase long-chain family members (ACSLs) has been a focus to normalize metabolic dysfunction in the liver. ACSLs catalyze the ligation of long chain fatty acids with coenzyme A to produce acyl-CoAs, which can subsequently undergo β-oxidation or be used for desaturation, synthesis of glycerolipid and cholesteryl ester, and protein acylation [9]. In the liver, ACSL1, ACSL4, and ACSL5 are predominantly expressed, with each isoenzyme exhibiting unique substrate selectivity and independently regulated expression [9]. This diversity contributes to their opposing roles in MASLD. During steatohepatitis, ACSL5 expression is downregulated, and silencing ACSL5 exacerbates hepatic lipid accumulation [10]. On the other hand, ACSL4 expression is elevated, and deletion of ACSL4 gene prevents steatosis, inflammation and fibrosis in the liver [11]. These contrasting results suggest that precise regulation of each ACSL enzyme is essential. However, due to the high structural similarity among these enzymes [9], targeting a specific ACSL subtype remains challenging. In this context, Hu et al. introduce ubiquitin-specific protease 29 (USP29) as a promising new approach [12].

USP family of deubiquitinases plays a key role in maintaining protein stability by removing ubiquitin chains from their substrates [12]. Since 1970s, research on protein ubiquitination in the liver has demonstrated significantly increased ubiquitinated proteins in steatotic liver [13,14], suggesting that the ubiquitination machinery could serve as an effective strategy to control expression of metabolic enzymes. In the current issue of Clinical and Molecular Hepatology, Hu et al. [12] show that USP29 maintains the stability of ACSL5 in the healthy liver. Specifically, they found that USP29 expression is decreased in both human and mouse livers with MASLD, paralleling a reduction in ACSL5 protein levels. Compared to wild-type mice, USP29 knockout mice showed increased hepatic fat accumulation, inflammation, and fibrosis, which were completely rescued by ectopic expression of ACSL5, indicating that the function of USP29 is entirely dependent on ASCL5. Interestingly, mass spectrometry identified ACSL5 as the sole USP29 substrate involved in fatty acid metabolism. Thus, their results propose USP29 as a novel therapeutic target for MASLD, which directly deubiquitinates ACSL5, thereby securing conversion of fatty acids to acyl-CoA (Fig. 1).

Based on the study by Hu et al. [12], one can expect that activating USP29 could offer a therapeutic benefit for reversing the dysregulation of fatty acid oxidation in MASLD patients. Yet, the findings may require cautious interpretation. In contrast to their results showing a protective effect of liver-specific ACSL5 overexpression against overnutrition, a previous study reported that whole-body ACSL5 knockout mice have reduced adiposity with increased energy expenditure [15]. This discrepancy may be partially attributed to the diverse roles of acyl-CoA, which serves not only as an energy source but also in protein acylation and production of signaling molecules [9]. In addition, the (non-) existence of other substrates should be investigated further to establish USP29 as a feasible target. Substrate selectivity of USP29 may vary depending on the pathophysiological conditions, which may confer opposing functions. Indeed, USP29 has been implicated in inducing chemoresistance through stabilizing hypoxia-inducible factor 1α in hepatocellular carcinoma [16]. Therefore, additional studies are needed to determine whether targeting USP29 will ultimately provide a successful therapeutic strategy for MASLD; nevertheless, the study by Hu et al. [12] has certainly opened a new and exciting avenue in specifically targeting the key metabolic enzymes in the liver.